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Optimal use of endocrine therapy in premenopausal patients with breast cancer

Which endocrine therapy?

Prudence Francis, from the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia, discussed which endocrine therapy is best for young, premenopausal patients.

She noted that the key differentiating factor in order to decide on a treatment option in this patient population is the risk of recurrence, and cited the findings of the Suppression of Ovarian Function Trial (SOFT) [1] as well as those of a joint analysis of SOFT and the Tamoxifen and Exemestane Trial (TEXT) [2].

In the SOFT trial, patients were randomly assigned to receive one of three regimens for 5 years: tamoxifen alone; tamoxifen plus ovarian function suppression (OFS; via treatment with the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy or irradiation); or tamoxifen with OFS and the aromatase inhibitor exemestane.

The study cohort was stratified by receipt or no receipt of chemotherapy, where the decision to withhold chemotherapy was made by the investigator on the basis of low-risk clinicopathological features, such as node-negative disease, tumour size no more than 2 cm and grade 1 breast cancer.

Among these low-risk patients, 5-year breast cancer-free survival was comparable for the tamoxifen monotherapy, tamoxifen plus OFS and tamoxifen plus OFS and exemestane treatment arms, at 95.8%, 95.1% and 97.1%, respectively. Five-year distant recurrence-free survival also did not vary significantly between the groups, with corresponding rates of 98.6%, 98.7% and 99.3%.

The speaker thus concluded that “for premenopausal women at low risk of recurrence, adjuvant tamoxifen alone is an appropriate treatment”, an option that was “probably underutilized” prior to the publication of the SOFT findings.

By contrast, for the women who had high-risk features considered to merit chemotherapy, exemestane plus OFS led to an absolute 7.7% improvement in the 5-year breast cancer-free interval and a 4.2% improvement in the 5-year distant recurrence-free interval compared with tamoxifen alone.

And a pooled analysis of the SOFT and TEXT trials, in which breast cancer patients were randomly assigned to receive 5 years of treatment with triptorelin plus either exemestane or tamoxifen, showed that exemestane significantly reduced the risk of disease recurrence by 28% relative to tamoxifen. Moreover, the risk of breast cancer recurrence was a significant 34% lower with exemestane than with tamoxifen.

Duration of endocrine therapy and modality of patient selection

Sung-Bae Kim, from the University of Ulsan College of Medicine in Seoul, Republic of Korea, focused on the duration of endocrine treatment in premenopausal breast cancer patients.

He explained that the benefits of 5 years of tamoxifen therapy are well known, with both reduction in recurrence and breast cancer mortality, but added that late recurrence “remains a challenge”.

The results of the landmark Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) [3] and the adjuvant Tamoxifen—To offer more? (aTTom) [4] trials suggest that extended tamoxifen is an option for women who remain premenopausal after 5 years of therapy.

In the ATLAS trial, the risk of breast cancer recurrence and breast cancer mortality was significantly lower for the women assigned to receive tamoxifen for 10 years than for those treated for 5 years, with an absolute reduction of 3.7% and 2.8%, respectively.

The UK-based aTTOm trial showed a similar significant reduction in breast cancer recurrence and mortality risk with 10 years compared with 5 years of tamoxifen treatment, with respective absolute differences of 2.6% and 1.4%.

However, the speaker pointed out that extended tamoxifen is associated with an increased incidence of endometrial cancer and pulmonary embolism, and that the side effects and personal cost should be discussed with the patient before continuing treatment.

For women who attain menopause during the initial 5 years of tamoxifen, the results of several trials – such as the MA-17, NSABP B-33 and ABCSG-6a – suggest that switching to an aromatase inhibitor may be more beneficial than continuing with extended adjuvant endocrine therapy, said the presenter.

He added that there are no data at present to support therapy with an aromatase inhibitor for longer than 5 years.

Sung-Bae Kim also commented on the issue of compliance, which he said is known to wane over time. In the ATLAS trial, for instance, adherence decreased from 100% at 5 years to 84% at 7 years, decreasing further with time.

Pregnancy during endocrine therapy

Discussing the issue of whether women with breast cancer can and should become pregnant, Sibylle Loibl, from the German Breast Group in Neu-Isenburg, Germany, stressed that doctors should not advise their patients against becoming pregnant after breast cancer.

Instead doctors should assess the general risk of relapse, and consider the prior and current treatment regimens, as well as age and menstruation history.

The type of therapy, for instance, can have a big impact on fertility. Jeanne Petrek et al [5] found that the combination of cyclophosphamide, methotrexate and 5-fluorouracil had the “most influence” on ovarian function, measured as the proportion of women menstruating, which “decreases dramatically” in the months after completion of chemotherapy. By contrast, women who received regimens containing less cyclophosphamide as well as those given regimens containing taxanes regained ovarian function fairly rapidly following the end of chemotherapy.

The presenter noted that pregnancy does not influence prognosis – a comparison of breast cancer survivors who did and did not become pregnant showed no significant difference in relapse-free survival [6]. Furthermore, there is “no best time to become pregnant”, she said, noting that Hatem Azim et al found no difference between disease-free survival among women who completed their pregnancy to term and those who had a termination or miscarriage and their matched nonpregnant counterparts.

But Sibylle Loibl cautions that these findings should not be considered a recommendation. She highlighted that additional prospective data are needed to determine the impact of interrupting endocrine therapy during pregnancy and a trial is currently underway to address this question.